The invention pertains generally to medical method/devices and more particularly to bioprosthetic heart valves, such as cryopreserved, pre-trimmed human homograft valves which have sewing rings formed of natural tissue (e.g., pericardial tissue, dura mater, tendon sheath, etc.) affixed thereto prior to cryopreservation.
Heart valve replacement surgeries have been performed in human beings for many years. In these surgeries, a patient""s diseased or malfunctioning heart valve is removed and a prosthetic valve is surgically implanted in its place. The available types of prosthetic heart valves include mechanical valves (i.e., valves constructed of non-biological materials such as titanium, carbon or steel) and bioprosthetic valves (i.e., valves formed fully or partially of biological tissue).
i. Heterografts vs. Homografts
Bioprosthetic valves include heterografts (also known as xenografts) as well as homografts (also known as allografts). Heterograft heart valves are formed of tissue that has been harvested from a non-human animal and subsequently implanted in a human recipient. Homograft heart valves are formed of valvular tissue that has been harvested from the heart of a human being and subsequently implanted in a human recipient.
Typically, heterograft heart valves are formed of tissue that has been harvested from the heart of an animal, such as a pig, and has been treated with a chemical fixative to preserve the tissue for subsequent implantation.
Typically, homograft heart valves are formed of tissue that has been harvested from cadaveric human donors, or from the explanted hearts of a human heart transplant recipients who""s ailing hearts had healthy valves despite the presence of cardiomyopathy or other cardiac pathology. The harvested homograft tissue is then treated chemically to kill any viruses or other microbes and subsequently cryopreserved (i.e., cooled to a very low temperature by immersion in liquid nitrogen) until the time of implantation. To date, commercially available homograft valves have typically been provided to the surgeon in a non-trimmed state (i.e., with a substantial amount of the donor""s muscle tissue (e.g., cardiac septal muscle) affixed to the valve). Thus, prior to implantation, the homograft must be removed from the liquid nitrogen freezer used for the valve bank, thawed by the method recommended by the manufacturer, and then carefully trimmed of excess tissue. This trimming process is laborious and not particularly standardized. Also, this trimming process typically must be performed by a highly trained surgeon.
Some bioprosthetic valves, known as xe2x80x9cstentedxe2x80x9d bioprosthetic valves, incorporate a man-made stent or support frame upon which preserved allograft tissue is mounted and an annular sewing ring, formed of man-made materials such (e.g., an annular nylon core covered with a knitted polyester sleeve), is formed about the inflow end of the valve to maintain the inflow end of the bioprosthesis in a non-collapsed xe2x80x9copenxe2x80x9d configuration and to provide a firm suture-holding strucure around the valve to facilitate suturing of the valve to the annulus of the recipient. U.S. Pat. No. 4,759,758 (Gabbay) has purported to describe a stented bioprosthetic heart valve formed of a man-made stent having chemically preserved biological tissue:(e.g., bovine pericardial tissue), mounted on the man-made stent to form the valve leaflets. Additionally, a quantity of preserved biological tissue or polyester (i.e., Dacron) that has been impregnated with collagen, is mounted about the base of the man-made stent to form a sewing ring thereon.
Examples of commercially available stented bioprosthetic valves include the Carpentier-Edwards(copyright), PERIMOUNT(trademark) Pericardial Bioprosthesis (Baxter Healthcare Corporation, Edwards CVS Division, P.O. Box 11150, Santa Ana, Calif. 92711-1150) as well as the Carpentier-Edwards(copyright) Porcine Bioprosthesis (Baxter Healthcare Corporation, Edwards CVC Division, P.O. Box 11150, Santa Ana, Calif. 92711-1150). Each of these valves are of the heterograft type.
Others, known as xe2x80x9cstentlessxe2x80x9d bioprosthetic valves, do not include any man-made stent or support frame, and are formed entirely of preserved biological tissue, and do not include any xe2x80x9csewing ringsxe2x80x9d formed about their inflow ends.
Examples of commercially available stentless bioprosthetic valves of the heterograft type include the Edwards Prima(trademark) Stentless Bioprosthesis (Baxter Edwards AG, Spierstrasse 5, CH-6848 Horw, Switzerland), the Medtronic Freestyle(trademark) Aortic Root Bioprosthesis (Medtronic, Inc. 7000 Central Avenue Nebr. Minneapolis, Minn. 55432-3576) and the St. Jude Toronto(trademark) SPV Stentless Bioprosthesis (St. Jude Medical, Inc. One Lillehei Plaza, St Paul, Minn. 55117).
An example of a commercially available stentless bioprosthetic valves of the homograft type is the CryoValve(trademark) cryopreserved aortic homograft (CryoLife Corporation, Atlanta, Ga.).
Stentless bioprosthetic valves may offer superior hemodynamic performance when compared to their stented counterparts, due to the absence of flow restrictions which can be created by the presence of a stent and/or sewing ring. Also, the stentless bioprosthetic valves may exhibit better post-implantation durability than the stented bioprosthetic valves, because they provide a more flexible structure which serves to dissipate stress during the cardiac cycle.
Stentless valves of the homograft type are particularly advantageous in that they exhibit excellent long-term durability and are completely devoid of synthetic or man-made components. The absence of such synthetic or man-made components has been demonstrated to minimize the likelihood of post-operative infection of homograft valves, even in patients who suffer from active endocarditis or other infectious processes within the thoracic cavity. However, the presently available homograft valves are associated with certain drawbacks, namely i) that they require a substantial amount of trimming by the surgeon prior to implantation and ii) the absence of a defined xe2x80x9csewing ringxe2x80x9d about the inflow end can cause surgeons to experience difficulty in firmly sewing the inflow end of the homograft valve to the patient""s native vale annulus.
Most bioprosthetic heart valves are formed at least partially of natural tissue that contains high concentrations of connective tissue proteins. Collagen, and to a lesser extent elastin, are the major connective tissue proteins which make-up the connective tissue matrix or framework of most biological tissues. The relative pliability or rigidity of each biological tissue is largely determined by its relative amounts of collagen and elastin and/or by the physical configuration (e.g., structural lattice) and confirmation of the connective tissue matrix.
At present, the natural tissue contained in most bioprosthetic heart valves is preserved, at the time of manufacture, by either chemical fixation (e.g., xe2x80x9ctanningxe2x80x9d) or by cryopreservation (e.g., cooling to a very low temperature by immersion in liquid nitrogen). Each of these tissue preservation techniques has certain advantages and disadvantages, as discussed more fully herebelow.
i. Chemical Fixation
The chemical fixation of biological tissues contained in bioprosthetic heart valves can be accomplished by contacting the tissue with one or more chemicals which will crosslink collagen and elastin molecules which are present within the tissue. Such crosslinking of the collagen and elastin serves to preserve the tissue so that it may be stored until it is needed for implantation in a patient. Examples of the types of biological tissues that are suitable for chemical fixation include cardiac valvular tissue, blood vessels, skin, dura mater, pericardium, ligaments and tendons. These anatomical structures typically contain connective tissue matrices, formed of collagen and elastin, and the cellular parenchyma of each tissue is disposed within and supported by its connective tissue matrix.
Each collagen molecule consists of three (3) polypeptide chains which are intertwined in a coiled helical confirmation. Chemical fixatives (i.e., tanning agents) used to preserve biological tissues generally form chemical cross-linkages between the amino groups on the polypeptide chains within a given collagen molecules, or between adjacent collagen molecules.
Elastin fibers are built by cross-linking (natural linkage) of repeating units of smaller molecules in essentially fibrous strands maintained by rigid cross-linking involving desmosine and isodesmosine. Those chemical fixatives which are used to form cross-linkages between the amino groups of collagen molecules also tend to form such cross-linkages between amino groups of elastin molecules. However, the amount of elastin present in most biological tissues is substantially less than the amount of collagen present therein.
When chemical cross-linkages formed between polypeptide chains within a single collagen or elastin molecule, such cross-linking is termed xe2x80x9cintramolecularxe2x80x9d, while cross-linkages formed between polypeptide chains of different collagen or elastin molecules are termed xe2x80x9cintermolecularxe2x80x9d.
The particular types of chemical fixative agents that have previously been utilized to cross-link collagen and/or elastin in biological tissues include; formaldehyde, glutaraldehyde, dialdehyde starch, hexamethylene diisocyanate and certain polyepoxy compounds.
Glutaraldehyde is the most widely used agent for fixing biological tissues to be as bioprostheses and there are currently a number of commercially available glutaraldehyde-fixed bioprosthetic devices, such as, heart valves of porcine origin having support frames or stents (Carpentier-Edwards(copyright) Stented Porcine Bioprosthesis; Baxter Healthcare Corporation; Edwards CVS Division, Irvine, Calif. 92714-5686), prosthetic heart valves formed of a metal frame having leaflets formed of bovine pericardial tissue mounted on said frame (e.g., Carpentier-Edwards (copyright)Pericardial Bioprosthesis, Baxter Healthcare Corporation, Edwards CVS Division; Irvine, Calif. 92714-5686) and stentless porcine aortic prostheses (e.g., Edwards(copyright) PRIMA(trademark) Stentless Aortic Bioprosthesis, Baxter Edwards AG, Spierstrasse 5, GH6048, Horn, Switzerland).
One problem associated with the implantation of bioprosthetic heart valves that have been preserved by chemical fixation is that they tend to undergo in situ calcification following implantation following implantation. Such calcification can result in undesirable stiffening, degradation and premature failure of the bioprosthesis. Both intrinsic and extrinsic calcification have been known to occur, although the exact mechanism(s) by which such calcification occurs is unknown.
The factors which determine the rate at which chemically-fixed bioprosthetic grafts undergo calcification have not been fully elucidated. However, factors which are thought to influence the rate of calcification include:
a) patient""s age;
b) existing metabolic disorders (i.e., hypercalcemia, diabetes, etc.);
c) dietary factors;
d) race;
e) infection;
f) parenteral calcium administration;
g) dehydration;
h) distortion/mechanical factors;
i) inadequate coagulation therapy during initial period following surgical implantation; and
j) host tissue responses.
Glutaraldehyde-fixed bioprosthetic grafts have been observed to calcify sooner than grafts which have been fixed by non-aldehyde fixative agents. Thus, non-aldehyde fixatives, such as polyepoxy compounds (e.g., Denacol Ex-810. Denacol Ex-313) may be useful for manufacturing bioprosthetic graft materials which exhibit improved (i.e., lessened) propensity for calcification.
Other techniques for mitigation calcification of implanted biological tissues are described in U.S. Pat. No. 4,885,005 (Nashef et al.) entitled Surfactant Treatment of Implantable Biological Tissue To Inhibit Calcification; U.S. Pat. No. 4,648,881 (Carpentier et al.) entitled, xe2x80x9cImplantable Biological Tissue and Process For Preparation Thereofxe2x80x9d; U.S. Pat. No. 4,976,733 (Girardot) entitled, xe2x80x9cPrevention of Prosthesis Calcificationxe2x80x9d; U.S. Pat. No. 4,120,649 (Schechter) entitled, xe2x80x9cTransplantsxe2x80x9d; U.S. Pat. No. 5,002,2566 (Carpentier) entitled, xe2x80x9cCalcification Mitigation of Bioprosthetic Implantsxe2x80x9d; EP 103947A2 (Pollock et al.) entitled, xe2x80x9cMethod For Inhibiting Mineralization of Natural Tissue During Implantationxe2x80x9d and WO84/01879 (Nashef et al.) entitled, xe2x80x9cSurfactant Treatment of Implantable Biological Tissue to Inhibit Calcificationxe2x80x9d; and, in Yi, D., Liu, W., Yang, J., Wang, B., Dong, G., and Tan, H.; Study of Calcification Mechanism and Anti-calcification On Cardiac Bioprostheses Pgs. 17-22, Proceedings of Chinese Tissue Valve Conference, Beijing, China, June 1995.
The overall biocompatability (e.g., antigenicity and immunogenicity) of the fixed graft material can significantly affect the severity of post-implantation graft calcification, and may also be a factor in the occurrence of other undesirable sequelae such as platelet activation, thrombogenesis, local inflammation, and/or graft failure.
iii. Cryopreservation
Cryopreservation is a tissue preservation technique wherein the tissue is cooled to an extremely low temperature and maintained in a frozen state. This cryopreservation of the tissue is typically accomplished by placing the tissue in a bath solution containing certain cryoprotectants (i.e., chemicals that protect the tissue from damage or degradation during freezing) and immersing it in liquid nitrogen to effect rapid and extreme cooling of the tissue and bath solution. The tissue then remains in the liquid nitrogen until it is desired to implant the tissue. At that time, the tissue is removed from the liquid nitrogen and thawed. Examples of specific cryopreservation techniques that have heretofore been used with homograft heart valves are described in U.S. Pat. No. 4,890,457 (McNally, et al) and U.S. Pat. No. 5,632,778 (Goldstein), the entire disclosures of which are expressly hereby incorporated by reference.
The present invention overcomes shortcomings of prior cryopreserved homograft heart valves by providing a pre-trimmed, specifically sized, cryopreserved homograft that has a sewing ring formed of cryopreservable natural tissue (e.g, pericardium) affixed at least partially about the inflow end of the homograft. Marking(s) may be formed on the natural tissue sewing ring to indicate a location(s) through which sutures may be passed to ensure that such sutures will engage (i.e., pass through) underlying annular connective tissue of the homograft.
Additionally, the present invention overcomes certain shortcomings of chemically fixed stentless heart valve bioprostheses of the prior art by providing a stentless bioprosthesis that has a sewing ring formed of natural tissue (e.g., pericardium) formed at least partially about the inflow end of the bioprosthesis. Such natural tissue sewing ring is less likely to become infected than other types of sewing rings made fully or partially of man-made materials, such as polyester mesh.